JAC Advance Access originally published online on January 14, 2009
Journal of Antimicrobial Chemotherapy 2009 63(3):534-542; doi:10.1093/jac/dkn530
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Original research |
Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa
1 Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo 143-8540, Japan 2 Division of Infection Control and Prevention, Niigata University Graduate School of Medical and Dental Sciences, Niigata University Medical School, Niigata 951-8510, Japan 3 Miyazaki Pharmacy Ltd, Nagasaki 852-8116, Japan
Received 7 September 2008; returned 18 October 2008; revised 8 December 2008; accepted 10 December 2008
* Corresponding author. Tel: +81-3-3762-4151 (ext. 2396); Fax: +81-3-5493-5415; E-mail: kazu{at}med.toho-u.ac.jp
Objectives: Multidrug-resistant Pseudomonas aeruginosa (MDRP) is becoming a serious problem in hospitals, especially in patients on ventilators. Recent data demonstrate that colistin may be effective for these patients, although limited in vitro and in vivo data are available. Our aim was to identify further characteristics of colistin for the therapy of pneumonia caused by MDRP.
Methods: The effects of colistin on clinical strains of MDRP were examined by susceptibility test, time–kill assay, lipopolysaccharide (LPS)-blocking assay and a mouse pneumonia model, alone or in combination with other antibiotics. For the pneumonia model, mice were intranasally infected with bacteria and kept in hyperoxic conditions to mimic ventilator-associated pneumonia.
Results: As a single agent, colistin exhibited the strongest activity of the antimicrobial agents tested. In combination, maximum synergy was observed with colistin plus rifampicin. As expected, co-incubation of bacterial culture supernatants with colistin significantly reduced LPS activities with an associated decrease in cellular cytotoxicity. In the pneumonia model, intranasal, but not intravenous, colistin combined with rifampicin produced maximum survival protection. Pharmacokinetic analysis of colistin demonstrated the superiority of intranasal administration, judging from the compartmentalized high concentration and the long half-life in the lungs. Moreover, colistin therapy significantly decreased both production of inflammatory cytokines and LPS activity, even at a dose effecting no change in the bacterial burden in the lung.
Conclusions: These data strongly suggest that colistin may be an important option for combination therapy against critical MDRP infections. For pneumonia especially, intranasal colistin with rifampicin may be beneficial not only for synergistic antibacterial activity, but also for blocking LPS.
Keywords: rifampicin , lipopolysaccharide , pharmacokinetics , cytokines